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With the advance of hardware and software, it has become routine to obtain trajectories that are tens of microseconds in duration, opening new opportunities for yet more rigorous and reproducible observations on mechanism. Toward this end, we presented a semi-automated analysis pipeline which operates on featurized simulation data, performs unsupervised clustering, and then identifies which input features are most discriminatory of cluster identity. Application of this pipeline to a large set of G-protein-coupled receptor simulation data shows that it identifies several well-known microswitches. Inspection of these structural elements reveals changes in conformation that are known to accompany functional transitions of the receptor. In addition to these known structural elements, the analysis also identifies functional transitions associated with one new motif\u2500the kink in transmembrane helix 2\u2500and discovers a coupled \u201cpiston-like\u201d motion of TM2 and TM3 that elaborates a previously reported motion of TM3.<\/jats:p>","DOI":"10.1021\/acs.jcim.6c01584","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T16:02:26Z","timestamp":1789488146000},"page":"11654-11669","source":"Crossref","is-referenced-by-count":0,"title":["Semi-Automated\nDiscovery of Structural Elements Controlling\nGPCR Function"],"prefix":"10.1021","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1324-3143","authenticated-orcid":true,"given":"Jingjing","family":"Ji","sequence":"first","affiliation":[{"name":"University of Delaware , , , ,","place":["Newark, Delaware, United States, 19716"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4590-0363","authenticated-orcid":true,"given":"Edward","family":"Lyman","sequence":"additional","affiliation":[{"name":"University of Delaware , , , ,","place":["Newark, Delaware, United States, 19716"]},{"name":"University of Delaware , , , ,","place":["Newark, Delaware, United States, 19716"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"issue":"D1","key":"2026092810074671500_cit1","doi-asserted-by":"publisher","first-page":"D425","DOI":"10.1093\/nar\/gkae1065","article-title":"GPCRdb in 2025: Adding Odorant Receptors, Data Mapper,\nStructure Similarity Search and Models of Physiological Ligand Complexes","volume":"53","author":"Herrera","year":"2025","journal-title":"Nucleic Acids Res."},{"issue":"4","key":"2026092810074671500_cit2","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1038\/s41573-024-01083-3","article-title":"Functional\nDynamics of G Protein-Coupled Receptors\nReveal New Routes for Drug Discovery","volume":"24","author":"Conflitti","year":"2025","journal-title":"Nat. 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